Many therapeutic agents, such as anthracyclines and vinca alkaloids, are especially effective in cancer chemotherapy. However, these agents often exhibit acute toxicity in vivo, especially bone marrow and mucosal toxicity, as well as a chronic cardiac toxicity in the case of the anthracyclines and chronic neurological toxicity in the case of the vinca alkaloids. Similarly, methotrexate may be used for the treatment of inflammatory reactions, such as rheumatic diseases, but its high toxicity limits its applications. Development of more and safer specific antitumor agents is desirable for greater effectiveness against tumor cells and a decrease in the number and severity of the side effects of these products (toxicity, destruction of non-tumor cells, etc.). Development of more specific anti-inflammatory agents is also desirable.
The search for more selective anticancer agents has been extremely active for many decades, the dose limiting toxicities (i.e. the undesirable activity of the anticancer agents on normal tissues) being one of the major causes of failures in cancer therapy. Accordingly, the goal has been to improve the specificity of anti-tumor agents for increased effectiveness against tumor cells, while decreasing adverse side effects, such as toxicity and the destruction of non-tumor cells.
The focus of research has been on the development of new therapeutic agents which are in the form of prodrugs, compounds that are capable of being converted to drugs (active therapeutic compounds) in vivo by certain chemical or enzymatic modifications of their structure. For purposes of reducing toxicity, this conversion is preferably confined to the site of action or target tissue rather than the circulatory system or non-target tissue. Prodrugs are often characterized by a low stability in blood and serum, due to the presence of enzymes that degrade or activate the prodrugs before the prodrugs reach the desired sites within the patient's body. A desirable class of prodrugs that addresses such problems has been disclosed in Trouet, et al., U.S. Pat. No. 5,962,216 and in Lobl, et al., PCT International Publication No. WO 00/33888, both of which are incorporated herein by reference.
Tripeptide derivatives of anticancer agents such as daunorubicin (“DNR”) and doxorubicin (“DOX”), to be used as prodrugs were studied by Chakravarty, et al., J. Med. Chem. 26:633-638, 1983 (A); Chakravarty, et al., J. Med. Chem. 26:638-644, 1983 (B); and Balajthy, et al., J. Med. Chem. 35:3344-3349, 1992. However, none of these approaches has been shown to be successful.
Other work in this area includes Monsigny, et al., FEBS Letters 119(1): 181-186, 1980 (DNR); Baurain, et al., U.S. Pat. No. 4,296,105 (DNR); Baurain, et al., J. Med. Chem. 23:1171-1174, 1980 (DNR); Masquelier, et al., J. Med. Chem. 23:1166-1170, 1980 (DNR); and de Groot, et al., J. Med. Chem. 42:5277-5283, 1999 (DNR and DOX), which all describe prodrugs comprising a carrier linked to the drug via a peptide arm. Typically, these references describe a peptide arm, linked via its free carboxyl function to the free amine function of derivatives of anthracyclines such as DNR. In addition, the arm of these prodrugs can be linked via its free amine function to a carrier consisting of a macromolecule (protein such as BSA, immunoglobulins, etc.) which permits the selective endocytosis of the prodrug by target cells.
However, in spite of the advances in the art, there continues to be a need for the development of useful prodrug compounds and methods of making such prodrugs. Prodrugs that display a high specificity of action, reduced toxicity, and improved stability in blood relative to known prodrugs of similar structure are particularly desirable. The instant invention addresses those needs.